BACKGROUND Human pancreatic β-cells are heterogeneous. This has been known for a long time and is based on various functional and morphological readouts. β-Cell heterogeneity could reflect fixed subpopulations with distinct functions. However, recent pseudotime analysis of large-scale RNA sequencing data suggest that human β-cell subpopulations may rather reflect dynamic interchangeable states characterized by low expression of genes involved in the unfolded protein response (UPR) and low insulin gene expression, low UPR and high insulin expression or high UPR and low insulin expression. SCOPE OF REVIEW This review discusses findings obtained by single-cell RNA sequencing combined with pseudotime analysis that human β-cell heterogeneity represents dynamic interchangeable functional states. The physiological significance and potential implications of β-cell heterogeneity in the development and progression of diabetes is highlighted. MAJOR CONCLUSIONS The existence of dynamic functional states allow β-cells to transition between periods of high insulin production and UPR-mediated stress recovery. The recovery state is important since proinsulin is a misfolding-prone protein, making its biosynthesis in the endoplasmic reticulum a stressful event. The transition of β-cells between dynamic states is likely controlled at multiple levels and influenced by the microenvironment within the pancreatic islets. Disturbances in the ability of the β-cells to transition between periods of high insulin biosynthesis and UPR-mediated stress recovery may contribute to diabetes development. Diabetes medications that restore the ability of the β-cells to transition between the functional states should be considered.

中文翻译：

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人胰腺β细胞的异质性。

背景技术人胰腺β细胞是异质的。这已经很长时间了，并且基于各种功能和形态学读数。β-细胞异质性可以反映具有不同功能的固定亚群。但是，最近对大规模RNA测序数据进行的伪时间分析表明，人类β细胞亚群可能反映的是动态可互换状态，其特征在于参与折叠蛋白反应（UPR）的基因表达低，胰岛素基因表达低，UPR低和高胰岛素表达或高UPR和低胰岛素表达。综述的范围这篇综述讨论了通过单细胞RNA测序结合伪时间分析获得的发现，即人β细胞异质性代表动态可互换的功能状态。强调了β细胞异质性在糖尿病发展和进程中的生理意义和潜在意义。主要结论动态功能状态的存在允许β细胞在胰岛素高产生期和UPR介导的应激恢复期之间转换。恢复状态很重要，因为胰岛素原是易错折叠的蛋白质，使其在内质网中的生物合成成为压力事件。β细胞在动态状态之间的转换很可能被控制在多个水平上，并受胰岛内微环境的影响。β细胞在高胰岛素生物合成和UPR介导的压力恢复阶段之间转换的能力受到干扰，可能有助于糖尿病的发展。